A group of scientists at The Scripps Research Institute have provided strong evidence that a popular hypothesis concerning the origins of a genetic mutation common among Caucasians of Northern European descent that protects against human immunodeficiency virus (HIV) is wrong.

The hypothesis suggests that the mutation conferred resistance against bubonic plague in the Middle Ages, much as it does against HIV today. This idea was based on the fact that the mutation first appeared around the same time that the "Black Death" plague epidemic killed a third of Europes population in the years 1346-1352. Since HIV was not present in Europe at this time, individuals with the mutation must have been protected against some other disease.

In a brief communication to be published this week in the journal Nature, Scripps Research Immunology Professor Donald Mosier and his colleagues show this hypothesis to be incorrect.

Mosier performed studies that demonstrate that the mutation does not protect against plague infection in mouse models and that it is unlikely to have offered any protection against the plague in humans during the Middle Ages.

An Important Receptor

The mutation in question is in the C-C chemokine receptor 5 gene, which makes the human receptor protein called CCR5. CCR5 is a seven trans-membrane spanning protein of 332 amino acids that inserts into the cell membranes of human CD4+ T helper cells. HIV particles use CCR5 to gain entry into CD4+ T cells.

The CCR5 32 mutation -- a deletion of 32 bases of DNA from the CCR5 gene -- was first identified in 1996 in individuals who seemed to be protected from infection with HIV despite having had multiple high-risk exposures to the virus.

The resistant individuals all had the 32-base pair mutation in their CCR5 genes, and that left them with CD4+ T cells with no CCR5 receptors, conferring resistance to HIV infection. Later data showed that individuals who were heterozygous for the mutation had lower CCR5 expression levels, less cell-to-cell infection, and brighter clinical prognoses.

In order to test the HIV/plague hypothesis, an attenuated, non-transmissible form of Yersinia pestis, the bacterial cause of plague, was tested on mice both with and without the CCR5 32 mutation. There was no difference in susceptibility between the two groups, says Mosier.

The possibility still exists, says Mosier, that the CCR5 32 mutation arose due to the influence of some other disease that was prevalent in the Middle Ages, such as smallpox. Mosier plans to address this possibility next.

The brief communication, "CCR5 mutation and protection against plague" was authored by Joan Mecsas, Greg Franklin,William A. Kuziel, Robert R. Brubaker, Stanley Falkow, and Donald E. Mosier and appears in the February 12, 2004 issue of the journal Nature.

This work was supported by the National Institutes of Health.

About The Scripps Research Institute

The Scripps Research Institute in La Jolla, California, is one of the worlds largest, private, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases and synthetic vaccine development.

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